Confectionery delivery system for actives

ABSTRACT

A chewable delivery system for actives comprising: 
     (a) an active pre-coated with at least one material selected from the group consisting of lecithin, polyoxyalkylenes having chain lengths of about 4 carbons or less, glycerides having a melting point of 100° C. or less, polyalkyleneglycols having a molecular weight of 3,700 or less, synthetic and natural waxes and mixtures thereof; and 
     (b) a confectionery matrix comprising a binder system comprising gelatin and a humectant material selected from the group consisting of glycerin and its lower alkyl (C 2-7 ) ester derivatives; a sweetener; and about 1% to about 30% by weight water.

FIELD OF THE INVENTION

The present invention relates to a novel confectionery delivery systemfor actives such as fiber and drugs. The confectionery delivery systemcomprises a chewable matrix and an active material, the combination ofwhich is preferably both fat free and non-sucrose-containing, andtherefore low in calories. Active materials such as dietary fiber and/ordrugs can be incorporated and effectively masked in the delivery system.The unpleasant taste and mouthfeel of the fiber and/or drug iseffectively masked and substantial hydration of the active is delayeduntil the delivery system passes through the oral cavity. The resultantproducts are substantially more palatable, and are essentially devoid ofgraininess, bitterness or fibrous texture. The pleasant taste of thedelivery system and products made therefrom encourages patientcompliance with a recommended therapy.

BACKGROUND OF THE INVENTION

Prescribed daily dosage amounts for fiber are often very high, requiringthe patient to administer the fiber or fiber composition several timesper day. While their benefits are well known to the consuming public,the unpleasant fibrous mouthfeel and texture of products containingdietary fiber have resulted in reluctance of patients to comply withprescribed dosages.

Patient compliance with prescribed drug therapies is also a problemparticularly when the drug has an unpleasant taste, after-taste orgritty mouthfeel. Drugs such as cholestryamine and potassium chlorideare known to taste unpleasant. The prior art has disclosed products tomask the taste of these drugs, but the products themselves often sufferfrom their own unpleasant tastes.

The trend, therefore, in patient use of the prior art productscontaining fiber or drugs has been to deviate from the prescribed dosageor frequency of dosage, thereby diminishing the effectiveness of thetherapy.

Two patents which disclose palatable drug formulations use coacervationtechniques to combine cholestyramine with modified celluloses. U.S. Pat.No. 3,974,272 shows oral palatable formulations containing aqueous mediaand cholestryamine. A method of treating hypercholesterolemia isclaimed. Chewable products containing cellulosic/gum colloids aredisclosed.

U.K. Pat. No. 1,446,352 concerns palatable compositions useful for thetreatment of hypercholesterolemia and biliary cirrhosis. The inventionprovides a liquid composition containing "coacervate of cholestyraminewith a cellulose hydrocolloid" derivative. By the term "coacervate" ismeant the coagulation of two hydrophilic substances of opposite charge.Representative hydrocolloids are methyl and ethyl cellulose, sodiumcarboxymethyl cellulose, hydroxyethyl cellulose and hydroxypropylcellulose. A water-insoluble dispersing agent, e.g., a substitutedcarboxymethyl-starch, is optional. In making the composition, 1 part byweight of hydrocolloid is combined with 4 to 10 parts of cholestyramineby dry mixing and passing through a No. 80 U.S. standard mesh screen.The resulting powder is then mixed with a liquid to form a coacervatewhich can be orally administered.

With respect to dietary fiber, numerous attempts to mask the fibrousmouthfeel have been tried. Various baked products, granola-type product,cereals and snack-food products have attempted to incorporate fiber inconfectionery systems. These products are generally high in caloricvalue and relatively low in dietary fiber. The objective of the priorart has been to attempt to conceal the unpleasant taste and texture ofthe fiber by using various materials such as fats, polyhydric alcohols,sugar solids or starch. While the objective is achieved to some degree,these materials increase the caloric value and dilute the effectivedose. High amounts of fiber, e.g., amounts greater than about 5%,typically were dry-tasting with an unpleasant fibrous mouthfeel.

Fiber products which are specifically intended for bowel normalizationand related disorders include those which are slurried in water. Withrespect to the prior art attempts to make a fiber product when is addedto water and drunk as a slurry, the fiber tended to clump together,forming slimy, unpalatable masses. These fiber clumps were comprised ofhydrated hydrocolloids, e.g., pysillium. High amounts of excipients werenecessary to minimize clumps. These excipients or dispersing aids weregenerally carbohydrate or fat materials such as sugar, dextrose and thelike, which are high in caloric value.

Conventionally, fiber is incorporated into edible substances as finepowder. There are several reasons for this. Fine powdered fiber is lessapt to form "fish-eye" clumps when hydrated, e.g., clumps having a drycenter and wet surface. Furthermore, the purification of fiber ofteninvolves steps which reduce the particle size of fiber. Few solubledietary fibers, with the exception of guar gum, hydrate sufficiently oruniformly unless the particle size is fine. Fine particles are, however,difficult to handle and process and products containing above 10 to 15%dietary fiber have unpalatable and fibrous textures.

It is well known that the functionality and effectiveness of fiber andcertain drugs such as ion exchange resins is dependent on the activesurface area. Fine particles achieve the desired therapeutic effectsmore effectively than course particles because the former have a highersurface area to weight ratio, e.g., a higher active surface. Forexample, in the case of ion exchange resins, e.g., cholestyramine, agreater surface area allows enhanced adsorption of bile acids, increasedion exchange, as well as other surface phenomena. In the case of fiber,increased surface area allows for increased adsorption of, andcombination with, liquids, body metabolites and the like. The result isincreased bulk and swelling upon adsorption which is therapeuticallydesirable.

While course substrate particles do not have sufficient effectivesurface area to be as effective as the finer particles, finer particlesalso suffer from certain handling, processing, and formulation problems.The finer particles, having a larger total surface area than courserparticles, tend to be organoleptically perceived as too dry or dusty,and in the case of certain fibers a pasty taste results. Theseorganoleptic characteristics are undesirable. Additionally, when fineparticles are added in therapeutic amounts to a delivery matrix, e.g, aconfectionery formulation, the fine particles tend to disrupt thecontinuous phase characteristics of the final product.

THE INVENTION

The present invention relates to a chewable delivery system for activessuch as drugs and fibers. The delivery system comprises:

(a) a water insolubilized active pre-coated with at least one materialselected from the group consisting of lecithin, polyoxyalkylenes havinga chain length 4 or less carbons, glycerides having a melting range ofabout 100° C. or less, polyalkylene glycols having a molecular weight ofabout 3,700 or less, synthetic and natural waxes and mixtures thereof;and

(b) a confectionery matrix comprising a binder system comprising gelatinand a humectant material selected from the group consisting of glycerinand its lower alkyl (c₂₋₇) ester derivatives; a sweetener; and moisturein the amount of about 1% to about 30% by weight.

It is critical to the success of the invention that effective masking ofbitterness and undesirable mouthfeel or texture be accomplished. Theactive materials therefore undergo a treatment prior to theirincorporation in the confectionery matrix. Pre-coating of the active isrequired using one or more of the recited materials. The term"pre-coating" is meant to refer to a variety of conventional techniqueswhich may be used to adhere to, create a film on, or otherwise coat theactive material prior to its incorporation in the confectionery matrix.Coating techniques useful include simple mixing, spray congealing,freeze-drying, fluidized-bed granulation, agglomeration, spray-coating,spray-drying and extrusion, as well as other encapsulation techniqueswell defined in the art.

The particular coating technique employed will depend to a large degreeon the type of active chosen. For example, if the active is a dietaryfiber, simple mixing or spray-coating is preferred. If the active is adrug such as cholestyramine, simple mixing or fluidized bed granulationmay be preferred.

The active is generally present in the final dosage form in therapeuticamounts commensurate with the type of drug or fiber used. Generally, theactive and pre-coating will make up about 15 to about 30% by weight ofthe total dosage form.

THE PRE-COATING MATERIALS

These materials must be capable of readily adhering and forming, atleast a partial, and preferably a full coating on the active. By doingso, the coating provides a barrier to aid in masking any bitternessand/or undesirable textural properties inherent in the active. Thebarrier also serves to protect the active, from a stability point ofview. The coating must, however, allow for proper release of the activeand must not interfere with the function or effectiveness of the active.The ratio of coating to active ranges from about 1:11 to about 99:1parts by weight.

Among those coating materials recited above, lecithin is preferredbecause of the numerous functions it provides. For example, theemulsifying character of lecithin aids in wetting of the active surfaceand facilitating its incorporation into the confectionery matrix, aswell as aiding in the miscibility of the active when hydrolyzed insolution or saliva. Pure grades of lecithin are preferred, e.g, onewhere the solids content is about 95% or higher. The lecithin should beof a fraction which is pourable, rather than powder or solid, at roomtemperature. The Condensed Chemical Dictionary, 9th edition, VanNostrand Reinhold, 1977, defines lecithin as mixtures of diglycerides offatty acids linked to the choline ester of phosphoric acid. Lecithinsare typically classified as phosphoglycerides or phosphatides. In theinstant coatings, lecithin preferably has a minimum of about 95% byweight of phosphatide present. This purity level is generally designatedin commercially available lecithins as "95% acetone insolubles." Thephrase "95% acetone insolubles" is intended to mean that upondissolution of the lecithin in acetone, 95% of the phosphatide portionremains insoluble. Residual impurities such as oil, moisture and solublenon-phosphatides account for the 5% of the material dissolves andextracted.

Those polyoxyalkylenes useful as the coating material for the activeinclude polyoxyethylene, polyoxypropylene, polyoxybutylene, copolymersof these, as well as mixtures thereof.

Glycerides which are useful as the coating material for the activeshould have a melting point or melting range of 100° C. or less, suchthat they soften in the mouth. The term "glycerides" used herein refersto commonly identified glycerides which are esters of glycerol and fattyacids in which one or more of the hydroxyl groups of the glycerol havebeen replaced by acid radicals. The glyceride is useful if a hydrophobiccoating on the active is desired.

Polyalkylene glycols useful as coatings for the actives includepolyethylene glycol, polypropylene glycol, polybutylene glycol andmixtures thereof, among others. As mentioned above, the molecular weightof the polyalkylene glycol should be about 3,700 or less.

Synthetic and natural waxes useful as coatings for the actives includeanimal waxes, vegetable waxes, petroleum waxes and the like. Specificexamples of waxes are beeswax, lanolin, bayberry, candelilla, carnauba,paraffin, microcrystalline petrolatum and carbowax. Mixtures of thesewaxes are also useful.

The pre-coating materials may be used in amounts of about 1 to about 10%by weight of the total delivery system and preferably in amounts ofabout 2 to about 6%.

THE ACTIVES

The term "active" means the fiber or drug materials referred to hereinwhich are incorporated into the confectionery delivery matrix either inthe pre-coated or uncoated form.

The term "edible" is meant to include all materials which are used by,or which perform a function in, the body. Thus, materials which are notadsorbed or absorbed are included as well as non-digestible anddigestible materials.

The term "fine" particle indicates a standard U.S. U.S. mesh size numberof greater than about 70. The term "coarse" particle indicates astandard U.S. mesh size number of less than about 70.

The term "dietary fiber" is understood to mean the component of foodwhich is non-digestible and non-metabolizible by humans. It is wellknown, however, that dietary fibers as they occur naturally in foodsources also have associated with them a small digestible portioncomprising fats, proteins, and carbohydrates.

Dietary fiber can be divided into two broad categories: insolubledietary fiber and water soluble dietary fiber. For purposes of thisinvention, "insoluble dietary fiber" means the water insoluble portionof an edible material remaining after chemical and enzymatic treatmenthas removed proteins, fats and carbohydrates. For example, brans,celluloses, hemicelluloses lignin and the like, are among those useful."Soluble dietary fiber" means dietary fiber which is the water solubleportion of an edible material remaining after the chemical and enzymatictreatment has removed proteins, fats and carbohydrates. For example,pectin, guar gum, locust bean gum, gum arabic, karaya gum and othersfrom the galacturonan and galactomannan classes; as well as psylliumseed gum, carageenan, konjac mannan, among others. These soluble fibershave been known to inhibit absorption of cholesterol in mammals, as wellas re-absorption of bile salts. The mechanism for this benefit isbelieved to be three-fold in nature. First, the shear mass of theswelled fiber occludes the cholesterol and bile salts, therebypreventing absorption. Second, the fibers will absorb the cholesteroland bile salts, thereby physically transporting out of the body.Finally, the fibers increase the transit time of stool bulk, whichdecreases the time in which absorption of cholesterol and bile salts canoccur. Dietary fiber provides the bulking effect commonly associatedwith fiberous materials.

Useful dietary fiber substrates include noncellulosic polysaccharides,pectin, gums, algal polysaccharides, cellulose, hemicellulose, lignin,mucilages and mixtures thereof. The dietary fiber is present in thedelivery system in amounts of about 1% to about 75% by weight;preferably in amounts of about 10 to about 30%; and most preferablyabout 12 to about 25%.

The term "drug" when used to classify the active includes medicaments,vitamins, mineral supplements and other chemical or biologicalsubstances intended for use in the treatment, prevention, diagnosis,cure or mitigation of disease or illness, or substances which affect thestructure or function of the body. Mixtures are operable.

Suitable categories of drugs that may be employed in the instantaggregate may vary widely and generally represent any stable drugcombination. Illustrative categories and specific examples include:

(a) Antitussives, such as dextromethorphan, dextromethorphanhydrobromide, noscapine, carbetapentane citrate, and chlophedianolhydrochloride;

(b) Antihistamines, such as chlorpheniramine maleate, phenindaminetartrate, pyrilamione maleate, doxylamine succinate, andphenyltoloxamine citrate;

(c) Decongestants, such as phenylephrine hydrochloride,phenylpropanolamine hydrochloride, pseudoephedrine, hydrochlorideephedrine;

(d) Various alkaloids such as codeine phosphate, codeine sulfate andmorphine;

(e) Mineral supplements such as potassium chloride and calciumcarbonates, magnesium oxide and other alkali metal and alkaline earthmetal salts;

(f) Laxatives, vitamins and antacids;

(g) Ion exchange resins such as cholestyramine;

(h) Anti-cholesterolemic and anti-lipid agents such as gemfibrozil;

(i) Antiarrhythmics such as N-acetyl-procainamide;

(j) Antipyretics such as acetominophen, aspirin and ibuprofen;

(k) Appetite suppressants such as phenylpropanolamine hydrochloride orcaffeine; and

(l) Expectorants such as guaifenesin.

Additional useful active medicaments include anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, anti-infectives, psychotropics, antimanics, stimulants,gastro-intestinal sedatives, antidiarrheal preparations, anti-anginaldrugs, vasodilators, anti-hypertensive drugs, vasoconstrictors andmigrane treatments, antibiotics, tranquilizers, antiphychotics,antitumor drugs, anticoagulants and antithrombotic drugs, hypnotics,sedatives, antiemetics, anti-nauseants, anticonvulsants, neuromusculardrugs, hyper- and hypoglycaemic agents, thyroid and antithyroidpreparations, diuretics, antispasmodics, uterine relaxants, nutritionaladditives, antiobesity drugs, anabolic drugs, erythropoietic drugs,antiasthmatics, cough suppressants, mucolytics, anti-uricemic drugs, andthe like.

Mixtures of the drugs and medicaments may also be used.

The preferred drugs are cholestyramine and potassium chloride.Cholestyramine is the chloride salt of a basic anion exchange resinwhich has an affinity for sodium chloride and a particularly strongaffinity for acid materials such as bile acids. It occurs as a whitepowder, insoluble in water and has an amine-like odor and a grittytaste. Cholestyramine is believed to absorb and combine with bile acidsin the intestine to form an insoluble complex which is then excreted bythe body. Cholesterol is the major precusor of bile acids which areformed by the oxidation of cholesterol. The serum level of cholesterolcan be reduced by administration of cholestyramine, which leads toreduction of bile acids and increased oxidation of cholesterol.

The recommended adult dosage of cholestyramine is about 5 to about 50grams per day; preferably about 12 to about 32 grams per day.Administration is generally about 3 or 4 times daily in dosages of about2 to 10 and preferably about 3 to 4 grams.

Potassium chloride is generally sold as a powder or tablet to bedissolved in cold water. Adult dosages are generally about 1.02 to about2.56 grams (40-100 MEq) per day, administered in amounts of about 50 MEqabout 1 or 2 times per day.

The drug is present in the delivery system in amounts of about 0.1 toabout 85% by weight; preferably about 5 to about 50%; and mostpreferably about 10 to about 30%.

THE CONFECTIONERY MATRIX

While the texture, physical attributes and form of the delivery systemcan be varied widely by alternating the ratio of ingredients within thegiven ranges, it is preferred that the delivery system be chewy inconsistency and texture. This "chewiness" is preferably smooth andcreamy in nature, although the courseness or smoothness may be balancedas desired.

This chewy delivery system is novel in that it is very different intexture and physical form from the prior art gels and nougats. This isprimarily due to the unique combination of ingredients and balance ofthe moisture content, which must be maintained within the range of about1 to about 30% by weight. Outside these ranges, the delivery systemfails to be operable. Too low a moisture content results in a brittleand crumbly product which is neither palatable or effective in maskingactives. At higher limits of moisture, microorganism growth becomes aproblem and the texture loses its chewiness. Water must be physicallytrapped in the structure of the delivery system in order to maintain thestructural integrity of the final product.

The binder system comprises gelatin and a humectant material which whencombined with the water provides structure to the delivery system. Thesweetener adds to the bulk as well as the sweetness of the deliverysystem.

The sweetener is generally selected from a wide variety of materials andis present in amounts of about 6 to about 70%, preferably about 30 toabout 50% and most preferably about 40 to about 45% by weight of thecomposition. Representative, but non-limiting examples of sweetenersinclude xylose, ribose, glucose, mannose, galactose, fructose, dextrose,maltose, partially hydrolyzed starch, lactose, hydrogenated starchhydrolysate and mixtures thereof. In addition to these sweeteners,polyhydric alcohols such as sorbitol, mannitol, xylitol, and the likemay also be incorporated as well as a variety of artificial sweeteners.Among those artificial sweeteners useful include amino acid basedsweeteners, dipeptide sweeteners, saccharin and salts thereof,acesulfame salts, cyclamates, steviosides, dihydrochalcone compounds,talin, glycyrrhizin and mixtures thereof.

The binder system contains gelatin in amounts of about 0.1 to about 5%and preferably about 0.5 to about 3.0% by weight of the final deliverysystem. A 250 bloom grade of gelatin is preferred, although not criticalto the practice of this invention. By the term "gelatin" is meant aheterogenous mixture of water-soluble proteins of high average molecularweight derived from collagen by hydrolytic action. The gelatin structureis modified by the incorporation of glycerin and its lower alkyl esterderivatives. Glycerin provides a water binding capacity to aid in themaintenance of the water balance. Glycerin is incorporated in amounts ofabout 0.1 to about 25% and preferably about 2% to about 9% by weight ofthe final delivery system. The combination of gelatin and the glycerinor glycerin derivatives provides a chewiness as well as structure to thefinal product. This combination is critical to the invention. Gelatinwithout glycerin or its derivatives would yield a composition and finalproduct which would have sufficient structural integrity as a product,but would lack the smooth, chewy texture necessary to obtain the propermouthfeel for masking the active materials. Without glycerin or itsderivatives the product would be too tough to chew and would not be aspalatable or attractive to the consumer. It is preferred that athermo-reversible gelatin be used to aid in obtaining homogeniety aswell as to provide processing convenience.

The delivery system in its final form can be classified as a semi-solid,intermediate moisture system, having some properties clearly identifiedwith those of gels and some properties that are similar to the nougatvariety of confectioneries. The inventive delivery systems are quitedistinguishable over conventional gels and nougats in texture, structureand chew properties.

Flavors which may optionally be added to the delivery system are thosewell known in the confectionery art. For example, synthetic flavor oils,and/or oils derived from plants, leaves, flowers, fruits and so forth,and combinations thereof are useful.

Representative flavor oils include spearmint oil, peppermint oil,cinnamon oil, and oil of wintergreen (methylsalicylate). Also useful areartificial, natural or synthetic fruit flavors such as citrus oilsincluding lemon, orange, grape, lime and grapefruit, and fruit essencesincluding apple, strawberry, cherry, pineapple and so forth.

The amount of flavoring agent employed is normally a matter ofpreference subject to such factors as flavor type, base type andstrength desired. In general, amounts of about 0.01% to about 5.0% byweight of the final product are useful with amount of about 0.02% toabout 1.5% being preferred and about 0.03% to about 1.2% being mostpreferred.

In a preferred embodiment, the inventive delivery system issubstantially fat-free and sucrose-free. This type of formulation isdesigned for those, who for dietetic reasons, are required to regulatetheir intake of fats and sugar. A typical preferred embodiment is asfollows:

    ______________________________________                                                                 Preferred range                                      Ingredient    % by weight                                                                              % by weight                                          ______________________________________                                        Lecithin      4.00       2.0-6.0                                              Cholestyramine                                                                              20.00      10.0-30.0                                            resin                                                                         Fructose      43.84      40.0-45.0                                            Sorbitol      12.00       8.0-45.0                                            Gelatin       1.00       0.5-3.0                                              Glycerin*     5.00       2.0-9.0                                              Hydrocolloid**                                                                              0.10                                                            Pectin        1.50        0-10                                                Citric acid   0.50        0.3-1.50                                            Flavor/color  0.06       0.03-1.2                                             Water         12.00       8.0-15.0                                            ______________________________________                                         *Anhydrous 99.5%                                                              **Represents 0.04% guar gum and 0.04% locust bean gum                    

This embodiment has been found to be particularly good for masking thegrittiness of the cholestyramine and is as effective as the prior artcholestyramine systems at delivering a clinically effect dosage of thedrug to the patient.

If the active is cholestyramine resin, an equilibrium must be maintainedwith respect to the water content of the delivery system. Theequilibrium relative humidity (ERH) of the confectionery matrix and thepre-coated cholestyramine must be approximately the same such thatlittle water exchange between the resin and the matrix occurs.Additionally, the matrix must be capable of preventing loss of moistureinto the atmosphere. Losing water from the matrix will cause the matrixto lose its unique chewy character and become brittle. Migration ofwater from the resin to the vehicle will cause the resin structure tocollapse, thereby destroying the resin channels necessary for bileabsorption.

The inventive delivery systems are prepared without excessive heat,e.g., lower than the boiling point of water, to maintain bound moisturein the cholestyramine resin.

OPTIONAL MATERIALS

The edible matrix of this invention may likewise contain additionalconventional additives, including fillers and mineral adjuvants such ascalcium carbonate, magnesium carbonate and talc; emulsifiers; coloringagents such as titanium dioxide; fats and oils such as partiallyhydrogenated palm kernel oil and coconut oil; starches such as modifiedcorn starch and tapioca dextrin as well as other conventionalconfectionery additives well known in the confectionery art.

In one embodiment compound coating, chocolate ingredients and the likehave been effectively employed in coating the delivery system. Forexample, the delivery system can be formed into a candy bar shape andenrobed with chocolate or caramel.

Hydrocolloid materials are optional but useful in the instant inventionas a texture modifier. The hydrocolloid is mixed into the deliverysystem in a hydrated or powder form. If the hydrocolloid is a dietaryfiber it is preferably added in powdered form. Upon hydration, e.g., insaliva, the hydrocolloid becomes slippery almost immediately. Thisslippery characteristic imparts lubricity to the particles to aid inmasking the active. The hydrocolloid thus modifies the physicalcharacteristics of the delivery system matrix. The hydrocolloidfunctions to bind fine particles of the active together and at higherconcentrations increases lubricity in the mouth. The lubricity isprimarily due to the slippery nature of the hydrated hydrocolloidsurface. This characteristic is an advantage in that the mouthfeelperception of the consumer is such that the particles are smooth andeasy to swallow, being devoid of unpleasant texture or taste.

The hydrocolloid material must, however, be one which does not interferewith the functionality of the active. For example, if an anion-exchangeresin such as cholestyramine is used as the active, nonionichydrocolloid materials such as guar gum or locust bean gum should beused. This is in contrast to the prior art cholestryamine patents, e.g.,U.S. Pat. No. 3,974,272, where anionics are added. If cholestyramine isused as the active in the inventive delivery systems, anionichydrocolloid materials are not useful since they would tend to bind withthe resin, leaving them less binding capacity to bind with bile resins.Other hyrocolloid materials are contemplated, however, with a variety ofother actives. Among those hydrocolloid materials useful include naturaland modified gums, e.g., locust bean gum, guar gum, carageenan, amongothers; celluloses and modified celluloses, pectin, mucilages, modifiedstarch, noncellulosic polysaccharides, algal polysaccharides andmixtures thereof.

Hydrocolloid materials are optionally present in amounts of about 0% toabout 0.1% and preferably in amounts of about 0.02 to about 0.06% byweight.

PROCESS OF PREPARATION

In general, the delivery system can be prepared by pre-coating theactive, and adding it to the confectionery matrix in a simple mixingprocedure. Pre-coating can be accomplished using any of theaforementioned coating techniques. With respect to preparation of theconfectionery matrix, gelatin and glycerin are first mixed together inwater along with any optional hydrocolloid materials, until uniformityis obtained. The sweetener(s) is/are then added, while mixing iscontinued, and the pre-coated active is then mixed in as well.Additional glycerin may be added at this point, along with flavor,color, pectin and other conventional ingredients. The final mixture isthen formed into the desired dosage piece size and wrapped fordistribution.

In the preparation of a typical preferred embodiment, e.g, the non-fat,non-sucrose cholestyramine resin example described herein, thecholestyramine is first separately coated with lecithin using a simplemixing technique. For example, the purified grade of lecithin is addedat ambient temperature, along with the cholestyramine resin to a Hobartmixer set at a medium mixing speed. The lecithin must be a liquidmaterial at room temperature such that it will flow around and coat thesolid resin particles. Adequate coating of the resin is obtained inabout 20 to 30 minutes.

In a separate container, preparation of the confectionery matrix isbegun by preparing an aqueous solution of guar gum and locust bean gum.A gelatin/glycerin aqueous solution is then added to the guar gum/locustbean gum solution and mixed until uniform. Fructose and sorbitol arethen dissolved in this solution and the pre-coated active is added atthis point. Additional glycerin, flavor, pectin, color and otherconventional confectionery additives may be added at this stage andmixing is continued until uniformity is obtained. The mixture is thenextruded using a Hutt twin screw extruder to form a bar-shapedconfiguration having a 20 gram weight. The product is then ready forpackaging.

The following examples serve to provide further appreciation of theinvention but are not meant in any way to restrict the effective scopeof the invention. All percentages throughout the specification andclaims are by weight of the final delivery system unless otherwiseindicated.

EXAMPLE I

Delivery systems were prepared in the manner discussed above, using thefollowing formulation:

    ______________________________________                                                 Delivery System - % Weight                                           Ingredient A       B        C     D      E                                    ______________________________________                                        Cholestyramine                                                                           20      25       30    35     40                                   resin                                                                         Lecithin   2.5     2.5      3.0   3.0    3.6                                  Fructose   40      40       38    35     30                                   Sorbitol   7       5        --    --     --                                   Mannitol   5       2        --    --     --                                   Guar gum   0.04    0.04     0.07  0.1    0.1                                  Locust bean gum                                                                          0.04    0.04     0.07  0.1    0.1                                  Water      16      16       18    16     16                                   Gelatin    2.5     2.5      3.0   3      3                                    Glycerin   5.22    5.22     6.16  6.1    6.0                                  Flavor     1.7     1.7      1.7   1.7    1.2                                             100     100      100   100    100                                  ______________________________________                                    

These formulations represent delivery systems which are non-fat,non-sucrose containing. The resultant mixtures were extruded intovarious shapes, e.g., bars and chunks, and tested for organoleptic andclinical efficacy. The results showed that each of the delivery systemformulations were effective in masking the taste of the drug andproviding a smooth texture devoid of graininess. Clinical tests showedeffective release and availability of the drug both in vitro and invivo.

EXAMPLE II

Delivery systems F and G were prepared having a laxative dosage ofdietary fiber as the active. The formulations were respectivelyidentical to formulation A and C of Example I, except that oat bran wassubstituted for the cholestyramine.

EXAMPLE III

Delivery systems were prepared according to the formulations below usinggemfibrozil and potassium chloride as actives.

    ______________________________________                                                    Delivery system* - % weight                                       Ingredient    H                 I                                             ______________________________________                                        Gemfibrozil   1.5     (300 mg)  --                                            Potassium chloride                                                                          --                6.4  (1.28 g)                                 Lecithin      2.5               3.0                                           Fructose      58.8              61.6                                          Sorbitol      7                 --                                            Mannitol      5                 --                                            Water         16                18                                            Gelatin       2.5               3                                             Glycerin      5                 6.3                                           Flavor        1.7               1.7                                                         100               100                                           ______________________________________                                         *Based on a 20 gram dosage piece.                                        

EXAMPLE IV

The delivery systems of this example demonstrate the use of sweetnersother than fructose.

    ______________________________________                                                         Delivery system*-                                                             % weight                                                     Ingredient         J       K                                                  ______________________________________                                        Cholestryamine resin                                                                             20.0    30                                                 Lecithin           2.5     3.0                                                Lycasin            52.00   --                                                 Polydextrose       --      37.5                                               Sodium saccharin   --      0.5                                                Guar gum           0.04    0.07                                               Locust bean gum    0.04    0.07                                               Water              16.0    18.0                                               Gelatin            2.5     3.0                                                Glycerin           5.22    6.16                                               Flavor             1.7     1.7                                                                   100     100                                                ______________________________________                                    

EXAMPLE V

This example demonstrates the use of a combination of dietary fiber(pectin) and cholestyramine as actives in the delivery system.

    ______________________________________                                                          Delivery system*-                                                             % weight                                                    Ingredient          L      M                                                  ______________________________________                                        Cholestryamine resin                                                                              15.0   20.0                                               Pectin              5.0    10.0                                               Lecithin            2.5    3.5                                                Fructose            40.0   38.0                                               Sorbitol            7.0    --                                                 Mannitol            5.0    .0                                                 Water               16.0   18.0                                               Gelatin             2.5    3.0                                                Glycerin            5.3    6.16                                               Flavor              1.7    1.7                                                ______________________________________                                    

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

We claim:
 1. A chewable confectionery delivery system for cholestyraminecomprising:(a) cholestyramine pre-coated with at least one materialselected from the group consisting of lecithin, polyoxyalkylenes havingchain lengths of about 4 carbons or less, glycerides having a meltingpoint of 100° C. or less, polyalkyleneglycols having a molecular weightof 3,700 or less, synthetic and natural waxes and mixtures thereof; and(b) a confectionery matrix comprising a binder system comprising fromabout 0.1% to about 5% by weight gelatin and a humectant materialselected from the group consisting of glycerin and its lower alkyl(C₂₋₇) ester derivatives, a sweetener; and about 1% to about 30% byweight water, all weights are in percent of the final delivery system.2. The delivery system of claim 1 wherein the material used for thepre-coating of the active is present in amounts of about 1 to about 10%by weight of the total delivery system.
 3. The delivery system of claim1 wherein the ratio of coating to achive is about 1:3 to about 1:8 partsby weight.
 4. The delivery system of claim 1 wherein the material usedfor the pre-coating of the active is selected from the group consistingof polyoxyethylene, polyoxypropylene, polyoxybutylene, copolymers ofthese and mixtures thereof.
 5. The delivery system of claim 1 whereinthe polyalkyleneglycol is selected from the group consisting ofpolyethyleneglycol, polypropyleneglycol, polybutyleneglycol and mixturesthereof.
 6. The delivery system of claim 1 wherein the binder systemcomprises about 0.1 to about 5.0% gelatin and about 0.1 to about 25% ofthe humectant material.
 7. The delivery system of claim 6 wherein thehumectant is selected from the group consisting of glycerine, triacetin,tributyrin and mixtures thereof.
 8. The delivery system of claim 1wherein there is additionally incorporated a nonionic hydrocolloid gum.9. The delivery system of claim 8 wherein the gum is selected from thegroup consisting of guar gum, locust bean gum, and mixtures thereof. 10.The delivery system of claim 1 wherein there is additionally included amaterial selected from the group consisting of pectin, sweeteners,flavorings, colorings, humectants, fillers, emulsifiers thickeners, andmixtures thereof.
 11. A method of treating hypercholesterolemia andrelated disorders comprising administering a therapeutically effectiveamount of the delivery system of claim
 1. 12. A method of preparing aconfectionery delivery system for cholestyramine comprising:(a)pre-coating the cholestyramine with at least one material selected fromthe group consisting of lecithin, polyoxyalkylenes having a chain lengthof about 4 carbons or less, glycerides having a melting point of 100° C.or less, polyalkyleneglycols having a molecular weight of 3,700 or less,synthetic and natural waxes and mixtures thereof, wherein the coatingdoes not interfere with the function or release of the active; and (b)preparing a confectionery matrix comprising the steps of (i) forming asolution of gelatin and a humectant selected from the group consistingof glycerin and its lower alkyl (C₂₋₇) ester derivatives; a sweetener;and about 1% to about 30% by weight water; and (c) admixing mixturesfrom (a) and (b) together; and (d) forming the resultant delivery systeminto shapes.
 13. The delivery system of claim 1 wherein the pre-coatedcholestyramine is present in a pharmaceutically effective amount. 14.The delivery system of claim 1 wherein the pre-coated cholestyraminecomprises about 15 to about 30% of the final product.
 15. A method oftreating hypercholesterolemia and related disorders comprisingadministering a therapeutically effect amount of a confectionerydelivery system comprising:(a) cholestyramine resin wherein thecholestyramine resin is coated with at least one material selected fromthe group consisting of lecithin, polyoxyalkylenes having 4 carbons orless, polyalkyleneglycols having a molecular weight of 3,700 or less andmixtures thereof; and (b) a confectionery matrix comprising a bindersystem comprising gelatin and a humectant material selected from thegroup consisting of glycerin and its lower alkyl (C₂₋₇) esterderivatives; a sweetener; and about 1% to about 30% by weight water. 16.The method of claim 15 wherein the pre-coating is conducted at roomtemperature and employs one of the following techniques: simple mixing,spray-coating; spray-congealing or fluidized-bed granulation.